Hydantoin manufacture



hydantoin.

Patented Aug. 14, 1951 HYDANTOIN MANUFACTURE Arthur 0. Rogers, Lewiston, N. Y., assignor to E. I. du vPont de Nemours & Company, Wilmington, Del., a corporation of Delaware No Drawing. Application March 11, 1947, Serial No. 733,995

- 'This invention relates to certain new hydantoins and 'to a novel process for the production thereof. The new compounds with which this invention is particularly concerned are 5-(deltachlorobutyl) hydantoin and 5-(delta-bromobutyl) It is one of the objects of this invention to provide a new and useful process for the production of 5-(delta-chlorobutyl) hydantoin and 5-(deltabromobutyl) hydantoin. Another object is to provide the new compounds fi-(delta-chlorobutyl) hydantoin and 5-(delta-bromobutyl) hydantoin.

It is a further object of the invention to provide an efficient and practical process for the production of the aforesaid compounds in high yields. These and other objects will be apparent from the following description of the invention.

The above objects are obtained in accordance with my invention which comprises reacting 5- (delta-hydroxybutyl) hydantoin with hydrogen chloride or hydrogen bromide. Preferably 5-(delta-hydroxybutyl) hydantoin is contacted with hydrogen chloride or hydrogen bromide at elevated temperatures.

In general I may proceed by passing hydrogen chloride into contact with 5-(delta-hydroxybutyl) hydantoin heated to a temperature sufficiently high to provide a liquid reaction medium.

Small amounts of water or other suitable matetact with hydrogen chloride until the melting point of a sample of the product reaches the correct' value or does not rise' with continued treatment. The reaction usually requires about 1 to hours depending upon the reaction conditions. In one embodiment of the invention, hydrogen chloride .is passed into contact with 5-(deltahydroxybutyl) hydantoin in the presence of water; The amount of water utilized should not be more than about 50% by weight of the reaction' mixture since in the presence .of greater amounts of water undesirable hydrolysis of the product may occur. In general I utilize sufficient water to lower the melting point of the reaction mixture to the desired temperature of operation or slightly lower. Usually about 10 to 20% water is sufl'icient.

In a preferred method of carrying out the invention, I utilize a reaction medium comprising a mixture of 5-(delta-hydroxybutyl) hydantoin and 5-(delta-chlorobutyl) hydantoin as I have found that the best yields are obtained in this manner and isolation of the product is simplified.

12 Claims. (Cl. 260-3095) p 2 .7 The concentration of'chlorobutyl hydantoin present is not critical and will vary as the reaction proceeds. Preferably sufiicient- 5-(delta-chlorobutyl) hydantoin is utilized so that the reaction mixture is liquid at the preferred operating temperatures. I have found it satisfactory to use equal weights of chlorobutyl hydantoin and hydroxybutyl hydantoin.

I prefer to operate the process of my invention at elevated temperatures and I have found that temperatures of to 200 C. are suitable. Preferably, I utilize temperatures within the range to C. for best results. At temperatures below 75 C. the reaction is slow while at temperatures above 200 C. decomposition may occur with resultant contamination of the product.

My novel process may be operated at atmospheric pressures with excellent results. However, if it is desired further to accelerate the reaction pressures greater than atmospheric may be utilized. Pressures of less than atmospheric may also be utilized if desired.

Although it is preferred to utilize gaseous hydrogen chloride or hydrogen bromide, these gases may be replaced in part by aqueous solutions as long as the total amount of water present in the reaction mixture does not exceed 50% by weight. If desired, catalysts may be used in the operation of my invention. Examples of suitable catalysts are catalysts of the amine salt type'and quaternary ammonium compounds as illustrated by pyridine, quinoline, tetramethyl ammonium chloride and trimethyl benzyl ammonium chloride.

The amine salts which are suitable are those compounds having the following general formula:

RaEN-X wherein each R substituent is hydrogen or an alkyl or aralkyl radical, Y is an alkyl radical and X is either chlorine or bromine. The preferred catalysts of this type are those amine salts which are aliphatic compounds in which at least two of the .R substituents in the above general formula are alkyl radicals. .That is, the. preferred catalysts of this class are the aliphatic tertiary amine hydrochlorides and amine hydrobromides and the use in the present invention are the hydrochlorides and hydrobromides of the following amines: mono-, diand tri-alkyl amines having from 1 to they are more readily available. Branched chain amines may also be used. Otherexamples of suitable amine hydrohalides are those in which the R substituents in the abcive foimulainclude at least one alkyl radical 'ln"additi'o'n to one or two aralkyl radicals such as the hydrochloride of dimethylbenzylamine. Examples 1 1 1", suitable quaternary ammonium salts are tetramethylammonium chloride, tetraethyl ammonium chloride and trimethylbenzyl ammonium chlori'de'andtlie like, especially those in 'which the alkyl radicals fcdntain not more than '6 {carbon atoms, and the co'rrs'po'ridirfglbro ifii 's. The preferred tertiary amine hydrolialid's and 'tetraalkyl ammonium halides are "illustrated byti'ia'rnylarnine hydrochloride, 'tetrame'thyl ammonium 'chloride, tetrathyl ammomum-cmorideana 'the corresponding H bromides. 1

.I-Ieterocyclic amine hydrochlorides whose molecular structure includes a "pyridine nucleus may also be utilized. "Pyridine hydrochloride fitself is highly *ifective 'as'a catalyst for the above reaction "and xcelleritre'sults 'may beattained byitsjluse. fOtherjcompounds which are suitable are the "hydrochlorides ofquinoline and isoquinoline and the v'arious alkyl derivatives of such compounds, for: example, 2-methylpyi'idine (alplia .picoli'ne), 3'me'thylpyr'idifie -(b'eta picoline), '25 methyletliylpyridine (aldehydine), 2- '.propylpyridine tcoriyrine) 2-'ethyl'-3,5-dimethylpyridine, falplia aim-venue) '2-methylquinoline (quinaldine) 'and 4-'methylquinoline (lepidine). When using catalysts of this type, I prefer to utilize :pyridine in; the form of its hydrochloride as I have roun -mat "excellent results are "obtained when using 'this catalys't which is readity available.

In addition -to the salts jof heterocyclic bases "described in theforegoi'ng "paragraph, the correspon'cling 1uaternary salts may be employed, for jexamplefalkyl ifpyridinium 'chlorides, etc. Heterocyclic 'bas'esfno t containing the pyridine nucleus may; also be used, for "example, piperidi'ne and other "hydrogenation "products of the pyridine deriyatives noted above, morpholine, N- 1ky1.morprionnesjpyri m, indole, pyrroli'dine, acridine, tiarbazole and hydrogenation 'or alkylation productsof .such compounds.

In general, any aliphatic, alicyclic or heterocyclic secondary or tertiary amine or quaternary ammoniumsalt may-beused...

The usei'of .catalys'ts permits effective operation at lower temperatures. I have found, for example,that1the best results iareobtained using pyridineiascatalyst at temperatures of about 90 to 100 C..inste'ad of the preferred temperatures of 115 to 135 C.'when operating the noncatalytic "process. .The reaction is also more rapid when a catalystis' used. In general, I prefer to utilize an amount'ofcatalyst which is about equal to the weight of the -(delta-l1ydroxybutyl) hydantoin. "Sinaller quantities may be used but for'effective results at least 10% by weight'basedon'theamount of 5-(delta-hydroxybutyl) fhydantoin should be present. Amounts of catalysts "greater than an equal weight may be utilized but without any apparent advantage. When utilizing catalysts of the types described above, it is desirable to have present sufficient water to maintain the hydrochlorides in solution. A slight excess of water may be present but it is necessary for best results to avoid'a concentrationof water greater than 50% by weight of the "reactionmedium.

Although I have found that the utilization of catalysts in the operation of my invention is efi'ective in-increasin the reaction rate and decreasing the temperature required, I- prefer to utilize a non-catalytic process utilizing a mixture of '5-(delta-hydroxybutyl) hydantoin and -'5-"(delta-chlorobutyl) hydantoin as the reaction :mediumsince excellent results are thus obtained andthe problem of separating and recovering a catalyst is avoided.

'It'is to be understood that although in the foregoing description I have referred to the preparation of. 151(delta-chlorobuty1). h danto ed within ithejs'copeof. thisinvention. The ('delta-bromobutyl). hydantoin is. prepar d ,int same manneras the .5.,-.(delta-chlorobutyl in! dantoin by utilizing hydrogen bromideiuthe place of hydrogen chloride as. desc i d. ab v fi-(deltaehydroxybutyll hydantoin whi h 51 used as the starting materialin. the-pmc ssiflf my invention is :a :new compound almonds-described i'n'my co-pending, application, Serial 1. 8.0. 732,653 filed' March 5,. 1947 (P.. TC. 2420)., .-;.I.n.-.on method described therein fi-idelta-hydroxybutyl) hydantoin is" prepared Joy ireacting delt hydmxy valeraldehyde with a Icompound 'yieldin'g cyanide ions, a compound yielding'narbonate ions-and --a compound yielding ammonium ions. -In;aipr.eferred method these-'compoundsgyielding cyanide ions, carbonate ions and. "ammonium ions are reacted with .a product mixture fobtained by. .113- drating .dihydropyranjn dilute:aqueous acid .medium. A specific example ,of the preparation, of 5-- (delta-hydroxybutyl). hydantoin as d escribed in my co-pending applicationzisas follows:

.Dihydropyran (3 .moles, 2.52 g). 'water ;(600 cc.).:an'd hydrochloric jacid .(15. cc. off-LN). were stirred together' until the dihydropyran was'gdissolved. ..The solution was icooledj and the, :flask sweptwith carbon dioxide. A'solutionxof 3. moles (15.3 ;g.) of sodiumcyanlde in .360 cc. water: was added slowly with stirring .under :car-bon. dioxide. vAmmonium hydroxide. (;3.3 moles; 22,0 :co.)

.was .added 'r'apidlyjarid stirring undercarbOn dioxide, continued at. 50 60? C.:.for 15 .hours. and

at 4041590. lOVGl' night. The mixture was-cooled and ,acidified with ,310 cc. .c'oncentrated hydrochloric acid. Two .hundredahd seventy i rams of pure 5-.(delta-hydroxybutyl) hydantoin-crysta'llized directly. Asecond crop containihg262 g. of the hydantoin mixed with s'odiumchloride was obtained by evaporating. the mother liquor. The totalryield was 5'7.2% ofjtheoreti'cal. The following examples illustrate 'irriy' invention:

, 'Ei'zidmfile '1 5-.(delta-hydroxybutyl) hydantoin {0.125 mole, 23.8 g.) twasjplaced inia test tube a'ndheatedjin an oil bath until melted. Hydrogenchlo'ride gas wasted in forq5 hours,.;h0ldin'g.;'the temperature at approximately USO-175 C. '.'Il'ie product was poured into cc. of waterfdissolvedby'heating-and cooled to"cry'stallize. Afterdryinggthe and melted at 122-123 C.

Example? q A mixture'of 1 mole (172 g.) 5'-(delta-hydroxybutyl) hydantoin and 25 cc. water was heated at approximately 115 -120 C. while stirring and feeding hydrogen'chloride gasfor'd /z hours. The product was poured into hot water and cooled to crystallize;-159 g. (83.4% of the theoretical yield of 5-(delta-chlorobutyl) hydantoin, melting at 123-124 C. was obtained.

Example Iiv 5.-(delta -hydroxybutyl) hydantoin (2 moles; 344 g.) and 5-(delta-chlorobutyl) hydantoin (344 g.) was heated to fusion by means of an oil bath, and hydrogen chloride was fed with stirring at 130-140 C. for 6.8 hours. Samples were removed periodically for melting point determination to follow the course of the reaction. These gave the following results:

Time (hours) M. P. 8 f ngxture A mixture of As indicated by the above results, the reaction was complete in 5 /2 hours; the yield was substantially quantitative.

In a similar experiment with smaller quantities and better gas-liquid contact, a quantitative yield of 5-(delta-chlorobutyl) hydantoin melting at l2'Z-l29 C. was obtained in 1 hour reaction time.

Example 4 Pyridine (50 g.) was saturated with hydrogen chloride gas and mixed with 0.5 mole (86 g.) of 5-(delta-hydroxybutyl) hydantoin. The mixture was heated in an oil bath and hydrogen chloride fed with stirring for 2 hours at approximately 125-130 C. The product was crystallized from 200 cc. water, to yield 90.3 g. (94.8% of theoretical) of B-(delta-chlorobutyl) hydantoin, melting at 127-l28 C.

Example 5 5-(delta hydroxybutyl) hydantoin (0.5 mole, 86 g.) and water (40 cc.) were heated to fusion in a water bath and gaseous hydrogen bromide passed in with stirring until it was no longer absorbed at an appreciable rate (2.4 hours). The product was poured into hot water and cooled to crystallize. The dried crystals weighed 104 g. (88.8% of theory) and melted at 128-129.5 C.; the melting point was unchanged by recrystallization from methanol.

Analyses of the products showed the chlorine and bromine contents to be in close agreement with the theoretical values. A recrystallized sample of 5-(delta-chlorobutyl) hydantoin was found to contain 18.47% chlorine. The calculated value for the compound is 18.60% chlorine. A sample of the 5-(delta-bromobuty1) hydantoin analyzed 33.8% bromine whereas the calculated value is 34.1%.

Both the bromo and the chloro compounds are soluble in hot water, methanol or ethanol and are sparingly soluble in these solvents cold. They are insoluble in most organic solvents, for example, ethers, ketones, hydrocarbons and lysine which was isolated as halogenated hydrocarbons... Thecompoundsdissolve in-agueousalkalies and maybe reprecipitat'edby acidification. The alkali metal salts of '5 (delta-chlorobuty1) hydantoin and 5,-(del-. ta-bromobutyl) hydantoin when heated alone or in solvents polymerizev with the elimination of the alkali metal halide. Upon hydrolysis, the polymer thus obtained is converted to lysine.

The identity of these new halobutylxhydantoins was further confirmed. by conversion .of 5-(delta-chlorobutyb .1.hydantoin .to 's-(deltaaminobu'tyl) hydantoin by treatment with ammoniaw The aminobutyl hydantoin was isolated as the hydrochloride which contained thecalculated quantity of ionizable chlorine. The aminobutyl hydantoin was hydrolyzed to yield the dihydrochloride and the monohydrochloride. Each of these compounds had the correct melting point and ionizable chlorine content.

The new compounds fi-(delta-chlorobutyl) hydantoin and 5-(delta-bromobutyl) hydantoin are useful as chemical intermediates for the preparation of other useful organic compounds. They are of particular utility in that they may be utilized for the synthesis of lysine, a material which is potentially of major commercial importance as a component as feed for live stock and which has not heretofore been available synthetically in commercial quantities.

I claim:

1. Process for the production of a 5-(deltahalobutyl) hydantoin which comprises reacting, as the sole reactants, o-(delta-hydroxybutyl) hydantoin with a material from the group consisting of hydrogen chloride and hydrogen bromide at a temperature between 75 C. and 200 C.

2. Process for the production of 5-(deltachlorobutyl) hydantoin which comprises reacting, as the sole reactants, s-(delta-hydroxybutyl) hydantoin with hydrogen chloride at a temperature between 75 C. and 200 C.

3. Process for the production of 5-(de1ta-bromobutyl) hydantoin which comprises reacting, as the sole reactants, 5(delta-hydroxybutyl) hydantoin with hydrogen bromide at a temperature between 75 C. and 200 C.

4. The process of claim 1 wherein the temperature is to C.

5. The process of claim 1 wherein the reaction is carried out in the presence of not more than 50% by weight of water based on the weight of the reaction mixture.

6. The process as defined in claim 1 wherein the reaction is carried out in the presence of a catalyst taken from the group consisting of amine salts and quaternary ammonium compounds.

7. The process of claim 5 wherein the reaction is carried out in the presence of .a catalyst.

8. The process as defined in claim 5 wherein the reaction is carried out in the presence of a catalyst taken from the group consisting of amine salts and quaternary ammonium compounds.

9. Process for the production of a 5-(deltahalobutyl) hydantoin which comprises reacting S-(delta-hydroxybutyl) hydantoin with a material from the group consisting of hydrogen chloride and hydrogen bromide at a temperature between 75 C. and 200 C. in the presence of not more than 50% by weight of water based on the weight of the reaction mixture and in the presence of pyridine as a catalyst.

10. In a process for the production of a 5- (delta-halobutyl) hydantoin, the step which sw ar;

comprises reacting. as the sele renam 5- (delta'*-hydroxybutyl) hydentoin with a material from the group consistingof hydrogen chloride and hydrogen bromide in the presence 01- a;- mixture of 5-(delta=hydroxybutyl) hydantoin and acompound takenfrom the group consisting of 5-(delta chlorobutyl) hyda'ntoin and fi-(deltabromobutyL) hydantoin at a temperature between 75 6.. and 200 C. V A V 11. The process sis-defined in claim. 10 .wherein the reaction is carried out inthe presence'ot a catalyst taken tromthe group consis'tme of amine salts and quaternary em'momum compounds.

12. The process of claim 10 wherein the temperature is 115 to 135 C;

V ARTHUR 0. ROGERS.

REFERENCES CITED 'fhe fol l 'owi'ng references are or record in the me or this palfeiifz' Chem. Abst., v01. 27, D. 1924 citing Hoppe- SeYIer-Z'. Physiol. Chem. 214, pp. 267-270 (1933).

Comptes Rendus, vol. 197, pp. 1652-4654 (1933).

Henze et aL, Jour of Organic Chemistry (January 1943), pp. 1728.

Livaik'. 6& 1..- Journal American Chemical So- 

1. PROCESS FOR THE PRODUCTION OF A 5-(DELTAHALOBUTYL) HYDANTOIN WHICH COMPRISES REACTING, AS THE SOLE REACTANTS, 5-(DELTA-HYDROXYBUTYL) HYDANTOIN WITH A MATERIAL FROM THE GROUP CONSISTING OF HYDROGEN CHLORIDE AND HYDROGEN BROMIDE AT A TEMPERATURE BETWEEN 75* C. AND 200* C. 